Process for the Preparation of 6-(7-((1-Aminocyclopropyl)Methoxy)-6-Methoxyquinolin-4-Yloxy)-N-Methyl-1-Naphthamide and Synthetic Intermediates Thereof

ABSTRACT

A process for the preparation in high yields and purity of the compound 6-(7-((1-aminocyclopropyl)methoxy)-6-methoxyquinolin-4-yloxy)-N-methyl-1-naphthamide of formula (I) and of the pharmaceutically acceptable salts thereof is described. The process has various advantages over those previously described, in particular it avoids the use of acyl azide intermediates and their Curtius rearrangement. Novel intermediates useful for the preparation of compound (I) are also described.

This application is a divisional of U.S. application Ser. No.14/138,302, filed Dec. 23, 2013. U.S. application Ser. No. 14/138,302 isa divisional of U.S. application Ser. No. 13/256,722 filed on Sep. 15,2011, now U.S. Pat. No. 8,642,767. U.S. application Ser. No. 13/256,722is a 371 U.S. National phase of PCT/EP2010/001519 filed on Mar. 11,2010, which claims priority to and benefit of Italian Application No.MI2009A000397 filed on Mar. 16, 2009, all of which are incorporatedherein by reference in their entireties.

FIELD OF THE INVENTION

The present invention relates to a process for the preparation of6-(7-((1-aminocyclopropyl)methoxy)-6-methoxyquinolin-4-yloxy)-N-methyl-1-naphthamideof formula (I) and the pharmaceutically acceptable salts thereof. Afurther object of the invention are novel intermediates useful for thepreparation of compound (I).

Technological Background

WO 2008/112408 A1 and US 2008/0227812 A1 disclose angiogenesisinhibitors with quinoline structure, useful for the treatment ofneoplasias.

One of the disclosed products is6-(7-((1-aminocyclopropyl)methoxy)-6-methoxyquinolin-4-yloxy)-N-methyl-1-naphthamideof formula (I), described in example 3 of the above mentioned patentapplications.

According to said documents, compound (I) is prepared by removing thebenzyloxycarbonyl protective group from the compound benzyl1-((6-methoxy-4-(5-(methylcarbamoyl)-naphthalen-2-yloxy)quinolin-7-yloxy)methyl)cyclopropylcarbamate (II):

in acid medium or by hydrogenolysis, to give compound (I).

Compound (II) is obtained in a number of steps with different processesin which the benzyloxycarbonyl protected 1-amino-1-cyclopropylmethylmoiety is introduced by subjecting the acyl azide obtained from1-((6-methoxy-4-(5-(methylcarbamoyl)naphthalen-2-yloxy)quinolin-7-yloxy)methyl)cyclopropanecarboxylicacid of formula (III):

to Curtius rearrangement, in the presence of benzyl alcohol,

or by alkylation of6-(7-hydroxy-6-methoxyquinolin-4-yloxy)-N-methyl-1-naphthamide offormula (IV):

with 1-benzyloxycarbonylamino-1-methylsolfonyloxymethyl-cyclopropane offormula (V):

The above mentioned applications do not provide yields concerning boththe preparation of compound (II) by the two above mentioned reactions,and the conversion of compound (II) to (I).

Compound (III) is prepared by a process in which the1-carboxy-1-cyclopropylmethyl moiety is introduced in4-hydroxy-3-methoxyacetophenone as in the form of the ethyl ester,followed by formation of the 4-hydroxyquinoline ring and, finally, bythe introduction of the 1-naphthylcarboxyamido fragment.

It is well known that the reactions requiring the use of azides, such asthe formation of acyl azides, or Curtius rearrangement of the latter,are potentially hazardous as they involve risk of explosions, thereforethey are not suitable for use in preparations on large scale.

The synthetic methods reported in WO 2008/112408 and US 2008/0227812include, inter alia, a general synthetic scheme in which thecycloalkyl-alkyl portion of the products is introduced by reactionbetween a cycloalkyl-alkyl mesylate and an hydroxy or aminoacetophenone, followed by nitration to give a nitroacetofenone,reduction of the nitro group to amino group, formation of the4-hydroxyquinoline ring and further work up of the latter to the finalproducts. The above mentioned applications do not provide examples ofthe use of this process for compound (I) or the other describedproducts.

DISCLOSURE OF THE INVENTION

The present invention relates to a process for the preparation ofcompound (I) and the pharmaceutically acceptable salts thereof in highyields and purity. The process has various advantages over thosedescribed above, in particular it avoids the steps of formation of acylazide corresponding to the product (III) and its Curtius rearrangementto give the product (II). Furthermore, the invention provides novelintermediates useful for the preparation of compound (I).

An aspect of the invention is a process for the preparation of thecompound6-(7-((1-aminocyclopropyl)methoxy)-6-methoxyquinolin-4-yloxy)-N-methyl-1-naphthamideof formula (I):

or a pharmaceutically acceptable salt thereof,

comprising the following steps:

-   a) reaction of an amino-protected    1-amino-1-hydroxymethylcyclopropane of formula (VI):

in which R and R′ taken together with the nitrogen atom they are linkedto are a protected primary amino group,

with 4-hydroxy-3-methoxyacetofenone of formula (VII):

under Mitsunobu reaction conditions, to give a compound of formula(VIII):

in which R and R′ are as defined above;

-   b) nitration of a compound of formula (VIII) to give a compound of    formula (IX):

in which R and R′ are as defined above;

-   c) reaction of a compound of formula (IX) with a compound of formula    (XV):

HC(OR1)₂N(Me)₂  (XV)

in which R1 is a straight or branched C₁-C₆ alkyl or a C₃-C₆-cycloalkyl,to give a compound of formula (X):

in which R and R′ are as defined above and the line

means that the double bond of the beta-enaminoketone group can be in cisor trans configuration;

-   d) reduction of the nitro group of a compound of formula (X) and    concomitant cyclization to give a compound of formula (XI) which can    be in equilibrium with its tautomeric form (XIa):

in which R and R′ are as defined above;

-   e) conversion of a compound of formula (XI) or (XIa) to a compound    of formula (XII):

in which X is selected from Cl, Br or I and R and R′ are as definedabove;

-   f) reaction of a compound of formula (XII) with    6-hydroxy-N-methyl-1-naphthamide of formula (XIII):

to give a compound of formula (XIV):

in which R and R′ are as defined above;

-   g) deprotection of the protected primary amino group of compound of    formula (XIV) to give compound of formula (I);-   h) optional conversion of compound (I) to a pharmaceutically    acceptable salt thereof through known methods.

The primary amine function present in the compounds (VI) and(VIII)-(XII) can be protected by using any protective groups known andcompatible with the reaction conditions the above mentioned compoundsare subjected to. Examples of protective groups that can beadvantageously used are those for which in the compounds (VI) and(VIII)-(XII) R′ is hydrogen and R is selected from the group consistingof: benzyl optionally substituted at the aromatic ring with up to threesubstituents selected from the group consisting of halogen, cyano,trifluoromethyl; C₁-C₃ acyl or C₇-C₁₁ aroyl such as acetyl and benzoyl;C₁-C₃ sulfonyl or C₆-C₁₀ arylsulfonyl such as trifluoromethanesulfonyl,benzene sulfonyl, p-toluenesulfonyl; C₁-C₄ alkoxycarbonyl such asmethoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, allyloxycarbonyl;benzyloxycarbonyl optionally substituted at the aromatic ring with up tothree substituents selected from the group consisting of halogen, cyano,trifluoromethyl, such as benzyloxycarbonyl; or R′ is a tri (C₁-C₃alkyl)silyl derivative and R is C₁-C₄ alkoxycarbonyl orbenzyloxycarbonyl optionally substituted at the aromatic ring with up tothree substituents selected from the group consisting of halogen, cyano,trifluoromethyl, to form together with the nitrogen atom they are linkedto a N-silylated carbamate such as tert-butyl N-trimethylsilyl carbamate(Tetrahedron Lett., 1997, 38, 191); or R′ and R together with thenitrogen atom they are linked to form a phthalimido group.

Compounds (VI) are known or can be prepared with known methods. Somecompounds, for example the compound of formula (VI) in which R isbenzyloxycarbonyl, are also commercially available (China Gateway).

The reaction between a compound (VI) and 4-hydroxy-3-methoxyacetofenone(VII) to give a compound (VIII) takes place under the conditionscommonly used for the Mitsunobu reaction, a well known reaction(Synthesis 1981, 1-28; Org. React. 1992, 42, 335-656) which can be usedfor the preparation of alkyl aryl ethers under mild conditions.Compounds (VIII) can be prepared using any reagent commonly used in theMitsunobu reaction between a phenol and an alcohol. The preparation ofcompounds (VIII) is usually carried out using an equimolar amount or aslight molar excess of a phosphine and an azodicarboxylate or anazodiamide which can be used in the Mitsunobu reaction, with respect to3-hydroxy-4-methoxyacetofenone and compound (VI).

The latter are usually employed in equimolar ratios or in an excess upto 30% of compound (VI) with respect to 3-hydroxy-4-methoxyacetofenone.The reaction is usually carried out in an organic solvent, such astetrahydrofuran, dioxane, methylene chloride, or mixtures thereof.Examples of phosphines which can be used are trialkylphosphines, e.g.tributylphosphine and tri-tert-butilphosphine; dialkylarilphosphines,e.g. diethylphenylphosphine; diarilalkylphosphines, e.g.diphenylisopropylphosphine; triarylphosphines, e.g. triphenylphosphine,(4-dimethylaminophenyl)diphenylphosphine anddiphenyl(2-pyridyl)phosphine.

Examples of azodicarboxylates are dimethylazodicarboxylate,diethylazodicarboxylate, diisopropylazodicarboxylate anddibenzilazodicarboxylate. Examples of azodiamides are theN,N,N′,N′-tetramethylazodicarboxyamide and1,1′-(azodicarbonyl)dipiperidine. A triarylphosphine, for exampletriphenylphosphine, is preferably used as the phosphine. Diisopropylazodicarboxylate is preferably used as the azodicarboxylate. Thereaction is preferably carried out in tetrahydrofuran at a temperaturebetween −10° C. and 10° C., preferably at 0° C., first contactingtriphenylphosphine and diisopropylazodicarboxylate, then adding4-hydroxy-3-methoxyacetofenone and finally compound (VI).

The nitration of a compound (VIII) to give a compound (IX) can beperformed using the conventional conditions for the nitration ofaromatic derivatives. The reaction is usually carried out at atemperature ranging from −5° C. to 5° C., preferably at 0° C., using amixture of concentrated nitric acid and acetic anhydride as thenitration reagent.

The reaction between a compound (IX) and a compound (XV) to give acompound (X) is usually carried out in an organic solvent selected fromtoluene, xylene, N,N-dimethylformamide, N,N-dimethylacetamide,N-methylpyrrolidone, or mixtures thereof, using a molar excess ofcompound (XV) at a temperature ranging from 50° C. to the boilingtemperature of the solvent and for a time comprised between 1 hour and24 hours. Compounds (XV) are known and commercially available. Thereaction is preferably carried out in N,N-dimethylformamide for abouttwo hours at a temperature of about 100° C., using 2 molar equivalentsof N,N-dimethylformamide dimethyl acetal with respect to compound (IX).

Transformation of a compound (X) into a 4-hydroxyquinoline derivative(XI) or into the tautomeric form of (XI) with 4-quinolone structure(XIa) is carried out by reductive cyclization using a modification ofLeimgruber-Batcho reaction, a reaction generally used for the synthesisof indoles (Organic Syntheses, 1985, vol. 63, 314) but also useful forthe synthesis of 4-hydroxyquinoline/4-quinolone derivatives, asdescribed in Tetrahedron Letters, 2005, Vol. 46, 735-737. All theprocedures and reagents able to reduce an aromatic nitro group to anamino group can be used, such as catalytic hydrogenation; hydrogentransfer hydrogenation, such as ammonium formate in the presence ofpalladium on charcoal; reductions with metals, e.g. zinc in acetic acid,iron in acetic acid, stannous chloride; sodium dithionite. For thepurposes of the invention, powder iron is preferably used as thereducing agent and the reaction is usually carried out at a temperatureof 80° C. in the presence of acetic acid as the solvent.

Compounds (XI)/(XIa) are transformed into compounds (XII) through wellknown reactions for the transformation of 4-hydroxyquinoline/4-quinolonederivatives into 4-alogenoquinoline derivatives. Reaction conditionswhich can advantageously be used comprise the use of phosphorousoxyhalide molar excess such as POCl₃ or POBr₃ to the compound of formula(XI)/(XIa), optionally in the presence of a solvent such as chloroformor methylene chloride and of an organic tertiary base such astriethylamine or diethylisopropylamine. The reaction is preferablycarried out using POCl₃ as the reaction solvent and operating at atemperature between about 60° C. and about 100° C., more preferably atabout 80° C.

The reaction of a compound (XII) with 6-hydroxy-N-methyl-1-naphthamide(XIII) to give a compound (XIV) can be carried out reacting an equimolaramount or a slight excess of compound (XIII) with respect to compound(XII) in an organic solvent such as ethyl acetate, tetrahydrofuran,dioxane, dimethylformamide, dimethylacetamide, N-methylpyrrolidone,dimethylsulfoxide, pyridine, 2,6-dimethylpyridine, optionally in thepresence of an inorganic base such as an alkali or alkaline-earth metalhydroxide or an alkali metal carbonate or bicarbonate, or in thepresence of an organic base such as triethylamine,diisopropylethylamine, pyridine or 4-dimethylaminopyridine. The reactionis usually carried out in dioxane or 2,6-dimethylpyridine at a refluxtemperature, in the presence of a 10-20% molar excess of compound (XIII)with respect to compound (XII), operating in the presence of a 5% molarexcess of 4-dimethylaminopyridine with respect to compound (XII).

Compound (XIII) is known and can be prepared according to known methods,such as that disclosed in WO 2008/112408.

The reaction of a compound (XIV) to give compound (I) consists in theremoval of the primary amino group protective group from a compound(XIV), using specific, well known methods, depending on the protectivegroup present. For example, when R′ is hydrogen and the R group ismethoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl,hydrolysis in acid medium is preferably used, such as treatment ofcompound (XIV) with an inorganic acid such as hydrochloric orhydrobromic acid or, for the tert-butoxycarbonyl group, treatment withan organic acid such as trifluoroacetic acid. The benzyloxycarbonylgroup can also be removed under hydrogenolysis conditions, by catalytichydrogenation or by hydrogen transfer hydrogenation. Thebenzyloxycarbonyl group is preferably removed in acidic conditions withhydrobromic acid in acetic acid, operating at a temperature ranging fromabout 20° C. to about 50° C., preferably at about 30° C.

Compound (I) can optionally be converted to a pharmaceuticallyacceptable salt thereof through conventional methods.

A further aspect of the invention is a process for the preparation ofthe compound6-(7-((1-aminocyclopropyl)methoxy)-6-methoxyquinolin-4-yloxy)-N-methyl-1-naphthamideof formula (I) or of a pharmaceutically acceptable salt thereof,comprising the following steps:

-   i) reaction between a compound of formula (VI):

in which R and R′ taken together with the nitrogen atom they are linkedto are a protected primary amino group, with a compound of formula(XVI):

in which X is selected from Cl, Br or I, under the Mitsunobu reactionconditions, to give a compound of formula (XII):

in which X, R and R′ are as defined above, followed by

-   ii) transformation of compound of formula (XII) into compound of    formula (I) through known methods.

The Mitsunobu reaction between a compound (VI) and a compound (XVI) canbe carried out under the conditions described above for the reactionbetween a compound (VI) and 4-hydroxy-3-methoxyacetofenone (VII). Acompound (XVI) in which X is Cl or Br is preferably used.

Compounds (XVI) can be prepared with known methods. For example,compound (XVI) in which X is Cl can be prepared according to whatdescribed in J. Med. Chem. 2008, 51, 5766-5779. Compound (XVI) in whichX is Cl is also commercially available.

Compounds (VIII), (IX), (X), (XI) and (XII) are novel and are a furtheraspect of the invention.

A further aspect of the invention is the use of compounds of formula(VIII), (IX), (X), (XI) or (XII) in a process for the preparation ofcompound (I) or of the pharmaceutically acceptable salts thereof.

The use of the Mitsunobu reaction for the preparation of compounds(VIII) has advantages over the alkylation of compound VII with themesylate obtained from compound (VI) disclosed in WO 2008/112408 A2 andin US 2008/0227812, such as milder reaction conditions (e.g. lowerreaction temperatures and reduced reaction times), improved yields,easiness of purification and purity profile of the obtained intermediate(VIII). In addition, the use of the Mitsunobu reaction between compound(VI) and compound (XVI) for the preparation of compounds (XII) providesan easy entry to the latter compound, which is overall more convenientthan the multistep process disclosed in the above mentioned patentapplications starting from the mesylate obtained from compound (VI).

The invention will be illustrated by the following examples.

EXAMPLES

The abbreviations reported in the following are used in the examples.All of the other abbreviations are conventional representations ofchemical formulae.

ACN: acetonitrile, AcOH: acetic acid, Ac₂O: acetic anhydride, DEAD:diethyl azodicarboxylate, DIAD: diisopropyl azodicarboxylate, DIPEA:diisopropylethylamine, DCM: dichloromethane, DMF: N,N-dimethylformamide,DMAP: 4-dimethylaminopyridine, DMSO: dimethylsulfoxide, AcOEt: ethylacetate, EtOH: ethanol, MeOH: methanol, THF: tetrahydrofuran, TEA:triethylamine, TFA: trifluoroacetic acid.

1H NMR spectra were recorded in the indicated solvent, using a BrukerAVIII500 spectrometer (Software: TOPSPIN VERSION 2.1; Probe: 5 mm PABBOBB-1H/D Z-GRD) or a Varian Mercuryplus300 spectrometer (Software:Vnmr6.1C; Probe: ID_PFG), operating, respectively, at 500 MHz and 300MHz. The following abbreviations were used: s, singlet; d, doublet; m,multiplet.

LC-spectra MS were recorded in the following conditions:

instrumentation: Agilent 1200&6110MS, ELSD Varian 380-LC.

column: Waters Sunfire C-18 50 mm×4.6 mm, 3.5 μm, termosthatized at 40°C.

mobile phase A: 0.05% TFA in water.

mobile phase B: 0.05% TFA in ACN.

Gradient:

Time (min) 0.1 1.70 2.60 2.70 % B 1 99 99 1

Flow: 3.0 mL/min.

Detector: UV @ 214 nm/bw 4 nm

-   -   UV @ 254 nm/bw 4 nm    -   MS    -   ELSD

Injection: 1 μl.

Analysis time: 2.7 min.

Example 1 Preparation of1-[(4-acetyl-2-methoxyphenoxy)methyl]-N-benzyloxycarbonyl-1-aminocyclopropane

A 10 L reactor equipped with mechanical stirrer was loaded withtriphenylphosphine (340.0 g, 1.296 mol) and THF (2 L) and the suspensionwas cooled with an ice bath. The stirred suspension was then slowlyadded with DIAD (264 g, 1.296 mol) over 30 minutes. After stirring for30 min at 0° C., the stirred suspension was added dropwise with asolution of 4-hydroxy-3-methoxyacetofenone (180 g, 1.08 mol) and DIPEA(210 g, 1.62 mol) in THF (1500 mL) The suspension was left understirring for 45 min at 0° C., then added dropwise with a solution of1-benzyloxycarbonylamino-1-hydroxymethylcyclopropane (China Gateway)(240 g, 1.08 mol) in THF (1500 mL) After 1 h, LC-MS analysis of a samplefrom the reaction mixture showed the complete disappearance of1-benzyloxycarbonylamino-1-hydroxymethylcyclopropane. The reactionmixture was evaporated and the crude product was recrystallized withEtOH 95% (4000 mL) to give1-[(4-acetyl-2-methoxyphenoxy)methyl]-N-benzyloxycarbonyl-1-aminocyclopropane(214 g, yield: 53.5%) as a white solid.

¹H-NMR (300 MHz, CDCl₃): δ: 7.41-7.45 (m, 2H), 7.26 (s, 5H), 6.77 (d,1H), 5.43 (s, 1H), 5.00 (s, 2H), 4.04 (s, 2H), 3.82 (s, 3H), 2.49 (s,3H), 0.92 (m, 4H).

LC-MS: M+H⁺: 370.4

The following compounds were prepared analogously:

-   1-[(4-Acetyl-2-methoxyphenoxy)methyl]-N-ethoxycarbonyl-1-aminocyclopropane;-   1-[(4-Acetyl-2-methoxyphenoxy)methyl]-N-tert-butoxycarbonyl-1-aminocyclopropane.

Example 2 Preparation of1-[(4-acetyl-2-methoxy-5-nitrophenoxy)methyl]-N-benzyloxycarbonyl-1-aminocyclopropane

A solution of HNO₃ (65%, 3 mL) in Ac₂O (2 mL) at 0° C. was slowly addedwith a suspension of the compound of Example 1 (1.1 g, 2.9 mmol) in Ac₂O(3 mL) After stirring at 0° C. for 2 h, the reaction mixture was pouredinto 50 mL of ice/water and the precipitate was recovered by filtration.The resulting yellow solid was recrystallized with 95% EtOH (5 mL) togive1-[(4-acetyl-2-methoxy-5-nitrophenoxy)methyl]-N-benzyloxycarbonyl-1-aminocyclopropane(0.69 g, yield: 56%) as a yellow solid.

¹H-NMR (300 MHz, CDCl₃): δ: 7.52 (s, 1H), 7.26 (s, 5H), 6.67 (s, 1H),5.36 (s, 1H), 5.02 (s, 2H), 4.05 (s, 2H), 3.86 (s, 3H), 2.42 (s, 3H),0.94 (m, 4H).

LC-MS: M+H⁺: 414.41

The following compounds were prepared analogously:

-   1-[(4-Acetyl-2-methoxy-5-nitrophenoxy)methyl]-N-ethoxycarbonyl)-1-aminocyclopropane;-   1-[(4-Acetyl-2-methoxy-5-nitrophenoxy)methyl]-N-(tert-butoxycarbonyl)-1-aminocyclopropane.

Example 3 Preparation of1-[(4-(3-dimethylaminopropenoyl)-2-methoxy-5-nitrophenoxy)methyl]-N-benzyloxycarbonyl-1-aminocyclopropane

A mixture of the compound of Example 2 (1.7 g, 4.1 mmol) andN,N-dimethylformamide dimethylacetal (0.9 g, 8.2 mmol) in DMF (6 mL) wasstirred at 100° C. for 2 h. After cooling at room temperature, thereaction mixture was diluted with water (30 mL) and extracted with AcOEt(3×50 mL) The combined organic phases were washed with brine (2×50 mL),dried and evaporated to give1-[(4-(3-dimethylaminopropenoyl)-2-methoxy-5-nitrophenoxy)methyl]-N-benzyloxycarbonyl-1-aminocyclopropane(1.9 g, yield: 95%) as a yellow solid.

¹H-NMR (300 MHz, CDCl₃): δ: 7.50 (s, 1H), 7.27 (s, 5H), 6.75 (s, 1H),5.44 (s, 1H), 5.23 (s, 1H), 5.11 (br, 1H), 5.01 (s, 2H), 4.04 (s, 2H),3.83 (s, 3H), 2.78-3.00 (m, 6H), 0.94 (m, 4H)

LC-MS: M+H⁺: 470.49

The following compounds were prepared analogously:

-   1-[(4-(3-Dimethylaminopropenoyl)-2-methoxy-5-nitrophenoxy)methyl]-N-ethoxycarbonyl-1-aminocyclopropane;-   1-[(4-(3-Dimethylaminopropenoyl)-2-methoxy-5-nitrophenoxy)methyl]-N-tert-butoxycarbonyl-1-aminocyclopropane.

Example 4 Preparation of1-[(4-hydroxy-6-methoxyquinolin-7-yloxy)methyl]-N-benzyloxycarbonyl-1-aminocyclopropane

A mixture of the compound of Example 3 (1.5 g, 3.2 mmol) and powder iron(1.8 g, 32 mmol) in AcOH (15 mL) was stirred a 80° C. for 2 h. Thereaction mixture was cooled at room temperature, diluted with AcOEt (150mL), filtered and washed with 50 ml of AcOEt. The filtration liquorswere combined, washed with water (2×100 mL) and an NaHCO₃ saturatedsolution (2×100 mL), dried and evaporated to give1-[(4-hydroxy-6-methoxyquinolin-7-yloxy)methyl]-N-benzyloxycarbonyl-1-aminocyclopropane(1.2 g, yield: 95%) as a yellow solid.

¹H-NMR (300 MHz, MeOD): δ: 7.75 (d, 1H), 7.51 (s, 1H), 7.15 (m, 5H),6.80 (br, 1H), 6.20 (d, 1H), 4.97 (s, 2H), 4.05 (s, 2H), 3.84 (s, 3H),0.87 (m, 4H).

LC-MS: M+H⁺: 395.2

The following compounds were prepared analogously:

-   1-[(4-Hydroxy-6-methoxyquinolin-7-yloxy)methyl]-N-ethoxycarbonyl-1-aminocyclopropane;-   1-[(4-Hydroxy-6-methoxyquinolin-7-yloxy)methyl]-N-tert-butoxycarbonyl-1-aminocyclopropane.

Example 5 Preparation of1-[(4-chloro-6-methoxyquinolin-7-yloxy)methyl]-N-benzyloxycarbonyl-1-aminocyclopropane

a) By Chlorination of the Compound of Example 4

A 50 ml round-bottom flask fitted with magnetic stirrer, thermometer,condenser and kept under nitrogen atmosphere, was loaded at 20°/25° C.with 3.90 g (9.89 mmol) of the compound of Example 4 and 25 ml of POCl₃.The resulting suspension became a solution after stirring for a fewminutes. The solution was heated at 85° C. inner T and after 30 minutesthe reaction was monitored by TLC, showing the disappearance of thestarting product. The solution was cooled and dropwise added, over about30 minutes and keeping the temperature below 10° C., to a mixture of 250ml of DCM and 250 ml of water, cooled at 0° C. After completion of theaddition, stirring was maintained for 30 minutes at 0°-10° C. The phaseswere separated and the aqueous phase was washed with 150 ml of DCM; thephases were separated and the organic phases combined. The combinedorganic phase was added with 150 ml of water, stirred at 20°/25° C. for15 minutes and pH was adjusted to 7-8 with a sodium bicarbonatesaturated solution. The phases were separated and the organic phase waswashed with 150 ml of water; the phases were separated, the organicphase was dried with sodium sulfate, filtered and the solvent evaporatedoff by distillation under vacuum. Stripping with ethyl ether afforded3.8 g of a brownish solid. The solid residue was dissolved in 20 ml oftert-butyl methyl ether, stirring at 20°/25° C. for an hour; filteredand washed with tert-butyl methyl ether, then dried to obtain1-[(4-chloro-6-methoxyquinolin-7-yloxy)methyl]-N-benzyloxycarbonyl-1-aminocyclopropane(3.4 g; yield: 87%) having (¹H-NMR) titre of 95%.

¹H-NMR (500 MHz, DMSO-d₆) δ ppm: 8.61 (d, 1H), 7.91 (s, 1H), 7.56 (s,1H), 7.44 (s, 1H), 7.38 (s, 1H), 7.29 (m, 5H), 4.99 (s, 2H), 4.23 (s,2H), 3.97 (s, 3H), 0.87 (m, 4H).

b) by Mitsunobu reaction between 4-chloro-7-hydroxy-6-methoxyquinolineand 1-benzyloxycarbonylamino-1-hydroxymethylcyclopropane

20 ml of DCM were added with 4-chloro-7-hydroxy-6-methoxyquinoline (300mg, 1.43 mmol; from China Gateway),1-benzyloxycarbonylamino-1-hydroxymethylcyclopropane (412 mg, 1.87 mmol,1.3 eq; from China Gateway) and triphenylphosphine (490 mg, 1.87 mmol,1.3 eq). The resulting solution was dropwise added with a solution ofDEAD (378 mg, 1.87 mmol, 1.3 eq) in 3 ml of DCM, keeping the temperatureat 0° C. for 2 hours. The mixture was then left at 10° C. for 20 hours,then filtered to recover the unreacted4-chloro-7-hydroxy-6-methoxyquinoline. The filtrate was evaporated undervacuum and the resulting residue was added with 20 ml of 95% EtOH andleft under stirring for 30 min. The solid was collected by filtration,washed with 5 ml of 95% EtOH and dried under vacuum to give1-[(4-chloro-6-methoxyquinolin-7-yloxy)methyl]-N-benzyloxycarbonyl-1-aminocyclopropane(273 mg; yield: 46%).

LC-MS: M+H⁺: 413.1

The following compounds were prepared analogously:

-   1-[(4-Chloro-6-methoxyquinolin-7-yloxy)methyl]-N-ethoxycarbonyl-1-aminocyclopropane;-   1-[(4-Chloro-6-methoxyquinolin-7-yloxy)methyl]-N-tert-butoxycarbonyl-1-aminocyclopropane.

Example 6 Preparation of benzyl1-[(6-methoxy-4-(5-(methylcarbamoyl)naphthalen-2-yloxy)quinolin-7-yloxy)methyl)]cyclopropylcarbamate (II)

A solution of 0.51 g (2.53 mmol) of 6-hydroxy-N-methyl-1-naphthamideprepared according to WO2008/112408, 2, 7 ml of 2,6-lutidine and 0.3 g(2.42 mmol) of DMAP, kept at 20°/25° C. and under nitrogen atmosphere,was added with the compound of Example 5 (1.0 g, NMR titre 95%, 2.30mmol). The suspension was heated to 140° C. inner temperature for 6hours; then cooled to 20°/25° C. and added with 80 ml of water and keptunder stirring a 20°/25° C. for 1 hour; the suspension was filtered andwashed with water, to afford 0.88 g (yield: 66%) of benzyl1-[(6-methoxy-4-(5-(methylcarbamoyl)naphthalen-2-yloxy)quinolin-7-yloxy)methyl)]cyclopropylcarbamate (II).

¹H-NMR (500 MHz, DMSO-d₆) δ ppm: δ: 8.56 (d, 1H), 8.50 (d, 1H), 8.39 (d,1H), 8.04 (d, 1H), 7.94 (s, 1H), 7.87 (s, 1H), 7.59 (m, 4H), 7.41 (s,1H), 7.44 (s, 1H), 7.30 (m, 5H), 6.56 (d, 1H), 5.01 (s, 2H), 4.48 (s,2H), 4.23 (s, 2H), 3.95 (s, 3H), 0.87 (m, 4H).

LC-MS: M+H⁺: 578.3

The following compounds were prepared analogously:

-   Ethyl    1-[(6-methoxy-4-(5-(methylcarbamoyl)naphthalen-2-yloxy)quinolin-7-yloxy)methyl)]cyclopropyl    carbamate;-   tert-Butyl    1-[(6-methoxy-4-(5-(methylcarbamoyl)naphthalen-2-yloxy)-quinolin-7-yloxy)methyl)]cyclopropyl    carbamate.

Example 7 Preparation of6-(7-((1-aminocyclopropyl)methoxy)-6-methoxyquinolin-4-yloxy)-N-methyl-1-naphthamide(I)

A mixture of the compound of Example 6 (0.24 g, 0.42 mmol) in 2 ml of asolution of 40% HBr in acetic acid was stirred at 30° C. for 3 h, thenadded with 10 ml of water and the reaction mixture was extracted withAcOEt (2×10 mL) The organic phases were removed. The aqueous solutionwas dropwise added with a solution of 50% NaOH to reach pH 10. Themixture was extracted with DCM (3×20 mL) and the combined organic phaseswere dried and evaporated to give a crude containing6-(7-((1-aminocyclopropyl)methoxy)-6-methoxyquinolin-4-yloxy)-N-methyl-1-naphthamide(I) with purity higher than >94% by LC-MS analysis. This crude wasfurther purified by chromatography on a silica gel column eluting withDCM/MeOH 10:1), to afford6-(7-((1-aminocyclopropyl)methoxy)-6-methoxyquinolin-4-yloxy)-N-methyl-1-naphthamide(I) having purity higher than 98% by LC-MS analysis (140 mg, yield:76%).

¹H-NMR (500 MHz, DMSO-d₆) δ ppm: 8.47 (d, 2H), 7.87 (d, 1H), 7.53 (m,3H), 7.51 (m, 1H), 7.44 (d, 1H), 7.38 (s, 1H), 6.50 (d, 1H), 6.16 (d,1H), 5.01 (s, 2H), 4.05 (s, 2H), 4.03 (s, 3H), 3.12 (d, 3H), 2.09 (m,2H), 0.80 (m, 4H).

LC-MS: M+H⁺: 444.0

1. A compound of formula (VIII):

wherein R′ is hydrogen and R is selected from benzyl, acetyl, benzoyl,trifluoromethanesulfonyl, benzenesulfonyl, p-toluenesulfonyl,methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, allyloxycarbonyland benzyloxycarbonyl optionally substituted on the aromatic ring withup to three substituents selected from halogen, cyano andtrifluoromethyl; or R′ is trimethylsilyl and R is tert-butoxycarbonyl;or R and R′ taken together with the nitrogen they are linked to form aphthalimido group.
 2. A compound of formula (IX):

wherein R′ is hydrogen and R is selected from benzyl, acetyl, benzoyl,trifluoromethanesulfonyl, benzenesulfonyl, p-toluenesulfonyl,methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, allyloxycarbonyland benzyloxycarbonyl optionally substituted on the aromatic ring withup to three substituents selected from halogen, cyano andtrifluoromethyl; or R′ is trimethylsilyl and R is tert-butoxycarbonyl;or R and R′ taken together with the nitrogen they are linked to form aphthalimido group.
 3. A compound of formula (X):

wherein R′ is hydrogen and R is selected from benzyl, acetyl, benzoyl,trifluoromethanesulfonyl, benzenesulfonyl, p-toluenesulfonyl,methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, allyloxycarbonyland benzyloxycarbonyl optionally substituted on the aromatic ring withup to three substituents selected from halogen, cyano andtrifluoromethyl; or R′ is trimethylsilyl and R is tert-butoxycarbonyl;or R and R′ taken together with the nitrogen atom they are linked toform a phthalimido group; and wherein the line

means that the double bond of the beta-enaminoketone group can be in cisor trans configuration.
 4. A compound of formula (XI) or (XIa):

wherein R′ is hydrogen and R is selected from benzyl, acetyl, benzoyl,trifluoromethanesulfonyl, benzenesulfonyl, p-toluenesulfonyl,methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, allyloxycarbonyland benzyloxycarbonyl optionally substituted on the aromatic ring withup to three substituents selected from halogen, cyano andtrifluoromethyl; or R′ is trimethylsilyl and R is tert-butoxycarbonyl;or R and R′ taken together with the nitrogen atom they are linked toform a phthalimido group.
 5. A compound of formula (XII):

wherein R′ is hydrogen and R is selected from benzyl, acetyl, benzoyl,trifluoromethanesulfonyl, benzenesulfonyl, p-toluenesulfonyl,methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, allyloxycarbonyland benzyloxycarbonyl optionally substituted on the aromatic ring withup to three substituents selected from halogen, cyano andtrifluoromethyl; or R′ is trimethylsilyl and R is tert-butoxycarbonyl;or R and R′ taken together with the nitrogen atom they are linked toform a phthalimido group.
 6. A compound as claimed in claim 1, whereinsaid compound is:1-[(4-Acetyl-2-methoxyphenoxy)methyl]-N-benzyloxycarbonyl-1-aminocyclopropane.7. Method of synthesizing a compound as claimed in claim 1 as anintermediate in the synthesis of6-(7-((1-aminocyclopropyl)methoxy)-6-methoxyquinolin-4-yloxy)-N-methyl-1-naphthamide(I) or a pharmaceutically acceptable salt thereof.
 8. A compound asclaimed in claim 2, wherein the compound is1-[(4-Acetyl-2-methoxy-5-nitrophenoxy)methyl]-N-benzyloxycarbonyl-1-aminocyclopropane.9. A compound as claimed in claim 3, wherein the compound is1-[(4-(3-Dimethylaminopropenoyl)-2-methoxy-5-nitrophenoxy)methyl]-N-benzyloxycarbonyl-1-aminocyclopropane.10. A compound as claimed in claim 4, wherein the compound is1-[(4-Hydroxy-6-methoxyquinolin-7-yloxy)methyl]-N-benzyloxycarbonyl-1-aminocyclopropane.11. A compound as claimed in claim 5, wherein the compound is1-[(4-Chloro-6-methoxyquinolin-7-yloxy)methyl]-N-benzyloxycarbonyl-1-aminocyclopropane.